Antisense therapy is a promising form of treatment for genetic disorders, infections, and other disorders in which a strand of complimentary nucleic acid (DNA, RNA or a chemical analogue) is used to bind to a target sequence within an DNA or RNA strand, such as messenger RNA (mRNA), to thereby inactivate a targeted gene. Antisense therapy has also been used to restore gene function by inducing exon skipping in mutated genes.
Oligomers, including natural oligonucleotides and chemically modified oligomers, have shown particular potential in antisense therapy. Currently, oligomers are being studied for the treatment of cancers (including lung cancer, colorectal carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes, ALS, Duchenne muscular dystrophy and diseases such as asthma and arthritis with an inflammatory component. Oligomers have also shown promise in the treatment of viral and bacterial infections.
Conjugating antisense oligonucleotide compounds with positively charged polymers has been shown to increase the effectiveness to which these molecules can be introduced into cells. However, conjugation with positively charged polymers has been associated with increases in toxicity. This is particularly problematic in cases where the effective therapeutic window of the antisense oligonucleotides lies close to the LD 50 dosage (dosage at which 50% of the experimental animals die). As a result, the use of antisense oligonucleotides has been limited.
Thus, there still exists a need for improved formulations for the administration of antisense oligonucleotides.